In Parkinson's disease (PD) the progressive degeneration of mesostriatal dopamine (DA) neurons eventually leads to motor symptoms, primarily hypokinesia, rigidity and tremor. Initially patients often derive sig- nificant benefit from L-DOPA treatment, though, many patients develop side-effects and in about 50% of patients the drug eventually looses its effectiveness. Our inability to prevent PD and the long-term ineffectiveness of L-DOPA therapy has prompted the search for new approaches to treatment. The overall goal of this proposed research is to develop a rational clinical approach for gene therapy of PD. This proposal was prompted by two of our findings. One, fibroblasts genetically modified in vitro to express tyrosine hydroxylase (TH) can correct a rat model of PD. Two, in vivo brain expression of reporter genes in transfected muscle cells that are transplanted intracerebrally was stable for at least two months and high levels of gene expression was achieved in muscle cells transplanted intracerebrally. This application proposes to explore the ability of genetically-modified primary muscle cells to serve as a feasible approach to gene therapy for brain diseases in general and PD specifically. Biochemical assays including TH enzyme assays and determination of monoamine concentrations in situ by HPLC detection techniques will be done. Also, expression of TH protein will be detected by immunohistochemical methods. These studies should eventually lead to new approaches for treating patients with PD but presently the studies will be restricted to animals.